Curcumin (diferulomethane) is a potent polyphenolic antioxidant, anti-inflammatory and anticarcinogenic compound that has gone through extensive pre-clinical testing in many different models for cancer and more recently for traumatic brain injury, stroke and other neurodegenerative diseases including work from our lab on Alzheimer's (AD). Relevant to AD, it has metal chelating and anti-amyloid aggregation activity and functions to inhibit the neuroinflammatory cascade (AP-1 transcription) and kinases involved in amyloid neurotoxicity. Based on efficacy and safety curcumin is currently in clinical trials for cancers and Alzheimer's, but the major issue that may limit its potential is relatively poor oral bioavailablity caused by poor solubility, pH dependent drug instability and high first pass metabolism through glucuronidation of the hydroxyls in the polyphenols. This proposal will use in vitro screens and animal models to address possible solutions to these problems with curcumin delivery, which are typical for many promising new drugs. Although we have an IND for curcumin for our pilot clinical trial, because of its excellent safety profile, systems of improved delivery need to re-address toxicity issues. We will use the Alzheimer transgenic model APPsw to evaluate efficacy Aim 1. We can greatly improve oral absorption of curcumin, using two preparations of micelles. Therefore we will evaluate the efficacy, bioavailability and toxicity of curcumin micelles Aim 2. Nanoparticles technology is becoming useful tools for improving the delivery of strongly hydrophobic drugs. Therefore we will evaluate the efficacy, bioavailability and toxicity of a curcumin lipid nanoparticles Aim 3. The major metabolite of curcumin (tetrahydrocurcumin, THC) has superior oral absorption and is a potent antioxidant. Therefore we will evaluate the efficacy, bioavailability and toxicity of the natural curcumin metabolite (tetrahydrocurcumin) Aim 4. A cognitive enhancing curcumin derivative (Salk Inst) with neuroprotective activity may enter clinical trials and gain approval fairly rapidly in short trials. A derivative of curcumin with brain derived neurotrophic factor (BDNF) mimetic properties has potent neuroprotective and cognitive enhancing properties. Therefore we will examine the efficacy, bioavailability and toxicity of the cognitive enhancing BDNF curcumin derivative in the APPsw mouse. Milestones. Year 1. Demonstration of formulations optimized for bioavailability (plasma, erythrocyte, brain levels). Year 2. Toxicology studies establish acute safety dosing and the dose response studies establish efficacy in acute in vivo models. Year 3. Long term (2 yr) safety studies completed and single dose efficacy for curcumin in long-term models. Year 4. Dose-response and behavior battery for curcumin completed in long-term models. Prepare for AD pilot clinical trial.